ABSTRACT Sickle cell disease (SCD) is a genetic disorder with profound consequences to families and the health care infrastructure. Notably, SCD can trigger nephropathy leading to end-stage renal disease (ESRD) with poor outcomes and no effective treatment. SCD-dependent susceptibility to ESRD is influenced by genetic factors. We demonstrated previously that MYH9 and APOL1, two loci in close physical proximity on chromosome 22, are independent predictors of proteinuria in SCD. This region, particularly two major risk alleles (named G1 and G2), has been replicated widely in non-SCD nephropathy. However, conflicting studies have suggested that alleles in either APOL1 or MYH9 might contribute to the pathology through an as yet unclear mechanism. Recently, we employed in vivo studies to understand the contribution of this locus to ESRD. We discovered a role for APOL1 in the developing zebrafish kidney and uncovered a complex genetic architecture, wherein the APOL1 G1 risk allele is a functional null while the G2 risk allele exerts a dominant negative effect. Critically, we also found that APOL1 and MYH9 interact genetically, in the context of anemic stress, potentially reconciling diverse observations about the roles of each gene in ESRD. These advances afford us the opportunity to probe key questions in the field, including: the spatiotemporal context involved in the pathology; the underlying cellular mechanisms and pathways that could be targeted for therapeutic intervention; and the extent to which other genetic factors contribute the SCD nephropathy. Equipped with potent, multidisciplinary working tools, including zebrafish mutants that recapitulate an experimentally tractable, physiologically relevant in vivo pathology, we propose three Aims. First, to examine the cellular pathology of the APOL1/MYH9 locus we will investigate the altered transcriptional networks in multiple relevant cell types in our APOL1 zebrafish models. Through this method, we will be able to query both suggested pathways, such as autophagy and altered chloride channel functionality and discover new ones in an unbiased fashion. Second, the absence of mechanistic knowledge in SCD nephropathy has limited therapeutic options. Although angiotensin-converting enzyme inhibitors (ACEi) appear to reduce albuminuria and are used widely, their efficacy in the context of APOL1 and SCD nephropathies remains unproven. We will screen our relevant APOL1 in vivo models for FDA-approved lead therapeutic compounds that could be transitioned rapidly into the clinical arena. Finally, although APOL1 and MYH9 convey critical risk for SCD nephropathy, there is clear evidence for additional genetic risk factors, the identification of which will likely inform pathomechanism. We will leverage our large SCD nephropathy cohort and our in vivo tools to identify additional susceptibility loci and, thus, provide potentially orthogonal entry points into the biology of this phenotype. Taken together, our studies will inform the pathomechanism underpinned by the MYH9/APOL1 locus, identify new drivers for SCD nephropathy and offer an exciting opportunity to identify lead compounds that will have both investigative and therapeutic potential.